The invention pertains to dextromethorphan tannate, its method of preparation and to pharmaceutical compositions containing dextromethorphan tannate.
Dextromethorphan (hereinafter also referred to as dextromethorphan free base) is a well-known commercially available compound. It is the methyl ether of the dextrorotary isomer of levorphanol, anarcotic analgesic. Its chemical name is 3-methoxy-17-methyl-9xcex1, 13xcex1, 14xcex1-morphinan and its CAS number is 125-71-3. It is a solid having a melting point of 109.5 to 112.5xc2x0 C. and its molecular formula is C18 H25NO. It is insoluble in water, and therefore is utilized typically in the form of its hydrobromide monohydrate salt that is soluble in water.
Dextromethorphan finds its principal use as an antitussive, i.e., a cough suppressant that acts centrally to elevate the threshold for coughing, but it does not have addictive, analgesic or sedative actions and does not produce respiratory depression with usual doses. It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions. It frequently is administered as an antitussive/expectorant composition consisting of dextromethorphan hydrobromide monohydrate and guaifenesin.
In contradistinction to the antihistamines, which are unstable in the form of their free bases, dextromethorphan is relatively stable. Therefore, little, if any attention, has been paid in recent years to improving dextromethorphan compositions. On the other hand, there is a considerable amount of prior art which has emerged in recent years directed to salts of antihistamines, principally tannate salts. For example, see U.S. Pat. Nos. 5,599,846; 5,663,415; 6,037,358; 6,287,597; and 6,306,904.
U.S. Pat. No. 3,282,789 is directed to stable liquid colloidal tannate compositions. Examples 1-6 of this patent disclose formulations containing dextromethorphan tannate. However, no mention is made in the ""789 patent as to the physical properties of the dextromethorphan tannate employed in the formulations nor is there any disclosure as to the method by which the dextromethorphan tannate was prepared. The patentees allude to several related patents involving the preparation of tannates of other materials by reacting a material with tannic acid in the presence of isopropyl alcohol employed as a solvent in the reaction mixture (such preparatory method is hereinafter referred to as the xe2x80x9cIPA routexe2x80x9d). Furthermore, the state of the art at the time of this patent was that tannates were always prepared by the IPA route. Such state of the art is also disclosed in one or more of the five U.S. patents identified above. Therefore, it is reasonable to assume that the dextromethorphan tannate employed in the examples of the ""789 patent was prepared using the IPA route.
Tannic acid is commercially available and is used in many industrial applications. It is frequently referred to as gallotannic acid, gallotannin; glycerite or tannin. It is a pale tan powder having a decomposition point of 210-215xc2x0 C., and is highly soluble in water and alcohols. Its molecular formula is C76H52O46; its CAS number is 1401-55-4. Tannic acid is typically produced from Turkish or Chinese nutgall and has a complex non-uniform chemistry and typically contains about 5-10 wt. % water.
Dextromethorphan is quite stable and therefore would not require the addition of a material such as tannic acid to render it stable. Due to its water insolubility, dextromethorphan must, however, be utilized in the form of a salt, typically the hydrobromide monohydrate salt (hereinafter referred to as xe2x80x9cdextromethorphan hydrobromidexe2x80x9d or xe2x80x9cdextromethorphan-HBrxe2x80x9d). However, dextromethorphan hydro-bromide does have a drawback: it is readily absorbed in the patient""s body, but its action is relatively short-lived. Accordingly, while it provides relatively quick cough sup-pression relief to the patient, the patient is required to take relatively high doses several times a day until the condition which necessitated the administration of the dextro-methorphan hydrobronide has been alleviated.
It would be very desirable if a form of dextromethorphan was available which would have extended-release properties, i.e., the dextromethorphan would be slowly released into the patient""s bloodstream over a prolonged period of time. Thus far, the only slow-release forms of dextromethorphan, which are available, are those such as polymer-coated tablets. Such prior art formulations provide mixed results in that the dextromethorphan is not available for adsorption into the patient""s bloodstream until the polymeric coating has been dissolved, but thereafter the dextromethorphan is quickly absorbed and metabolized. The result is that frequently, the dextromethorphan hydro-bromide must again be administered to the patient within the period of only a few hours.
It has now been found that it is possible to provide an extended-release form of dextromethorphan by reacting it with tannic acid so as to form dextromethorphan tannate, which differs dramatically from commercially available dextromethorphan tannate, or dextromethorphan tannate synthesized using the IPA route.
The dextromethorphan tannate of the invention may be readily prepared by the following method:
Dextromethorphan free base is obtained from a commercial source or a commercially available dextromethorphan acid salt such as dextromethorphan hydrobromide is treated with an aqueous base, e.g., 10% sodium hydroxide, to release the free base which is then washed to remove any sodium salts contained therein.
Tannic acid is heated to a temperature in the range of about 80 to about 180xc2x0 C., preferably 110 to 150xc2x0 C., and the dextromethorphan free base is slowly added, while mixing, to the heated tannic acid slurry over a period of a few minutes to about one hour. Since the reaction mixture becomes very viscous and difficult to stir as the reaction proceeds, it is desirable to add about 5 to about 30%, preferably 5 to 15 wt. %, additional water before adding the dextromethorphan free base. The reaction mixture is continued to be stirred while maintaining such temperature range for a period of about 10 minutes to about 2 hours. Thereafter, the reaction mixture is cooled to room temperature. The resultant solid reaction mass comprising the dextromethorphan tannate is preferably thereafter milled to form a free-flowing powder preferably to a particle size of about 50 to about 200 mesh Since the dextromethorphan tannate product as prepared is moist, it may be dried to a moisture content of 5 wt. % or less by conventional methods, e.g., heat lamp, in a steam of air or nitrogen, vacuum drying, etc. at a temperature of about 20 to about 80xc2x0 C. for about 30 minutes to about 24 hours. However, the moisture content is relatively irrelevant in respect to its usage as a cough suppressant since the dextromethorphan tannate of the invention is intended to be ingested.
The molar ratio of the dextromethorphan free base to the tannic acid is generally in the range of about 4 to about 8, preferably 5-6, moles of dextromethorphan per mole of tannic acid.
The dextromethorphan tannate of the invention has the following physical properties: It has a softening point in the range of about 140xc2x0 C. when the product has a moisture content of about 3% and a softening point of about 100xc2x0 C. when the product has a moisture content of about 5% (the softening point is inversely related to the moisture content of the product). By contrast, commercially available dextromethorphan tannate has a softening point of about 174xc2x0 C. with a moisture content of about 5%, while dextromethorphan tannate synthesized via the IPA route has a softening point of about 172xc2x0 C. with a moisture content of about 5%. The dextromethorphan tannate of the invention is a tan-colored powder that is slightly soluble in water. The dextromethorphan free base is a white powder that is insoluble in water, while tannic acid is a tan powder that is soluble in water.
The dextromethorphan tannate of the invention in the form of particles having a particle size of about 100 mesh has a tap density in the range of about 0.7 to about 0.85 g/cc, while both commercial available dextromethorphan tannate and dextromethorphan tannate synthesized via the IPA route in the form of particles having the same mesh size have a tap density of about 0.4 g/cc, or lower.
A further and very important distinction between the dextromethorphan tannate composition of the invention relates to its purity level. Commercially available dextro methorphan tannate as well as dextromethorphan tannate synthesized using the IPA route contain relatively high levels of unreacted dextromethorphan free base, i.e., in the order of 2.5-6 wt. % (based on the weight of the dextromethorphan tannate) of unreacted dextromethorphan free base. In contra-distinction thereto, the dextro methorphan tannate of the invention contains substantially no unreacted dextromethorphan free base, i.e., the amount of such unreacted dextromethorphan free base in the dextromethorphan tannate composition of the invention will be less than 2 wt. %, typically less than 1 wt. % and often less than 0.5 wt. %.
Further distinctions between the dextromethorphan tannate of the invention and dextromethorphan tannate synthesized via the IPA route may be found by comparing the spectra obtained by FTIR analysis as shown in Example 8 below.
The dextromethorphan tannate of the invention may be prepared for oral administration in the form of pharmaceutically acceptable compositions such as powders, capsules, elixirs, syrups, etc. Preferably, the compositions are prepared in the form of tablets containing about 10 to about 100 mg of dextromethorphan tannate per tablet or as a suspension, i.e., a liquid, wherein each 5 ml (teaspoon) of liquid would contain about 5 to about 60 mg of the dextromethorphan tannate.
Tablets containing the unique dextromethorphan tannate of the invention may be prepared in a conventional manner by the addition of suitable pharmaceutical carriers, including fillers, diluents, lubricants and the like as well as conventional and well known binding and disintegrating agents. A typical tablet composition of the present invention will contain, in addition to the dextromethorphan tannate, microcrystaltine cellulose, corn starch, magnesium stearate, croscarmellose sodium and coloring matter.
The suspension formulations of the dextromethorphan tannate of the present invention will typically additionally contain citric acid, caramel, glycerin, sorbitol solution, propylene glycol, saccharin sodium, sodium benzoate, flavoring agent and purified water.
If desired, the dextromethorphan tannate of the invention may be formulated with other pharmaceutically active ingredients such as antihistamines and antitussives, e.g., chlorpheniramine, dexchlorpheniramine, brompheniine, dexbrompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbetapentane, carbinoxamie, guaifenesin, and the like. Typically, these other active ingredients will be employed in the form of their free bases or as their salts, e.g., citrates, maleates, hydrobromides, hydrochlorides, tannates, etc. Of course, the dosage of the dextromethorphan tannate of the present invention, alone or in combination with other pharmaceutically active ingredients to be administered, will be dependent on the age, health and weight of the recipient, types of concurrent treatment, if any, frequency of treatment and effect desired.